Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
Sci Rep. 2022 Mar 22;12(1):4867. doi: 10.1038/s41598-022-08516-2.
Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1 explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.
富含亮氨酸的α-2-糖蛋白 1（LRG1）是一种分泌性糖蛋白，在生理条件下主要由肝脏产生。在疾病状态下，其局部诱导促进了致病的新生血管形成，而其抑制则导致功能失调的血管生成减少。在这里，我们研究了白细胞介素 6（IL-6）在 LRG1 介导的血管生成缺陷中的作用。IL-6 处理可诱导内皮细胞和离体血管生成培养物中 LRG1 的表达，并促进血管生长，但壁细胞覆盖减少。然而，在 Lrg1 外植体中，IL-6 未能刺激血管生成，并且血管表现出改善的壁细胞覆盖。IL-6 通过 STAT3 的磷酸化和结合到 LRG1 启动子中的保守共有序列来激活 LRG1 转录，该序列的缺失消除了激活。使用抗 IL-6 受体抗体托珠单抗阻断人肺内皮细胞中的 IL-6 信号，可显著降低 LRG1 的表达。我们的数据表明，IL-6 通过 STAT3 磷酸化激活 LRG1 转录，导致血管不稳定。鉴于 IL-6 在 COVID-19 伴有严重肺微血管并发症的患者中的潜在作用，这一观察结果尤其及时，针对 IL-6 的治疗已被证明是有益的。然而，我们的数据表明，针对阻断下游血管病变效应分子 LRG1 的治疗可能更具效用。
